To date, the biological role of growth hormone binding protein (GHBP) remains largely unknown. While many theories have been put forth, there is no direct evidence that can identify a specific role for this protein. We and others believe that it is highly likely that the GHBP plays a significant role in the GH/IGF- 1 axis. The main argument for this is due to the convergent evolution of two distinct mechanisms in mammals to produce the same protein (i.e. in humans the GHBP is produced by proteolytic cleavage of the GH receptor (GHR) extracellular domain while in rodents GHBP is produced by alternative splicing of the GHR precursor mRNA). Thus, we believe that the best way to elucidate the function of the GHBP is to create a GHBP gene specific disrupted or "knockout" mouse line. Hence, the objective of this research is to create the first GHBP specific gene-disrupted mouse and then to determine the contributions of GHBP on the growth phenotype as well as other metabolic processes in these animals. Our laboratory has already disrupted the mouse GHR/BP genes and generated combined GHR/GHBP "knockout" mice. In the homozygous state, these mice display a dwarf phenotype and serve as a model for a human GH- insensitive state termed Laron Syndrome. Although these mice are dwarf and obese, they are extremely sensitive to the action of insulin, resistant to diabetic kidney damage and, surprisingly, they have an extended life span. With this animal providing a background, we are now ready to test the specific hypotheses concerning the in vivo importance of GHBP by isolated GHBP gene-deficiency using a targeted gene disruption approach. We are confident that many questions concerning the biological role of GHBP will be answered in addition to new questions being raised once the GHBP gene disrupted mouse is generated. This proposal seeks to elucidate the role of growth hormone binding protein (GHBP), a protein whose function remains largely unknown other than its ability to bind growth hormone (GH) in the blood. Unlike GHBP, the function of GH is well established and GH is known to play an important role in normal metabolism and in the progression of several diseases such as diabetes, cancer and even aging. Thus, results obtained from this proposal would not only further our understanding of GH, but could help further our understanding of complex metabolic conditions and of the processes involved in aging. [unreadable] [unreadable] [unreadable]